Archive for May, 2013

HOT – Taxol analogues offer promising new anti-cancer leads

In this HOT paper, K. C. Nicolaou and co-workers have developed a series of taxol analogues which show potent activity against several cancerous cell lines.

The fight against cancer is one of the hottest areas of drug discovery. Despite this, there is still a shortfall in treatment options and the disease is on the rise. The development of safer and more selective drugs is therefore required.

Paclitaxel (taxol) and docetaxel are two of the most highly successful anti-cancer drugs and much research has been performed focused on their synthesis and structure. K C Nicolaou and his group at Scripps are well-versed in the construction of paclitaxel; the group published one of the first total syntheses of this complex molecule in 1994.

10-Deacetylbaccatin III is an advanced synthetic precursor to paclitaxel and shares many its core structural features. Thanks to the synthetic efforts of recent years, it’s also readily accessible and therefore it provides an interesting starting point for further structure-activity relationship studies. Nicolaou and Valiulin have found that, upon treatment with diethylaminosulfur trifluoride (DAST), 10-deacetylbaccatin III undergoes a nifty vinylogous pinacolpinacolone rearrangement leading to a new enone structure and its fluorinated analogue.

Nicolaou and Valiulin have capitalised on this discovery and have prepared an small library of structurally analogous taxoids using this reaction. The library of analogues was submitted to screening program run by the National Cancer Institute (NCI) where the compounds were evaluated against 60 different cancerous cells lines. Several of the taxoids showed significant potency against numerous tumour cell lines. This study has revealed important information regarding the structure-activity relationship of the taxoid family of molecules. It has also produced some promising potential leads for new anti-cancer drugs.

Synthesis and Biological Evaluation of New Paclitaxel Analogs and Discovery of Potent Antitumor Agents

Synthesis and Biological Evaluation of New Paclitaxel Analogs and Discovery of Potent Antitumor Agents
Kyriacos C. Nicolaou and Roman A. Valiulin
DOI: 10.1039/C3OB40654G

Free to access for 4 weeks

Digg This
Reddit This
Stumble Now!
Share on Facebook
Bookmark this on Delicious
Share on LinkedIn
Bookmark this on Technorati
Post on Twitter
Google Buzz (aka. Google Reader)

The power of multivalency against cholera

An international team of scientists has synthesised a cholera inhibitor that matches both the valency and target sugar of the cholera toxin. The molecule is 100,000 times better at trapping the cholera toxin than inhibitors based on the target sugar alone.

Cholera is an acute intestinal infection that can be fatal in severe cases. It is caused by the cholera toxin, a protein with a disease causing A subunit, surrounded by five B subunits. The B subunits bind to GM1, a pentasaccharide sugar, on the cell membrane of intestinal cells. Once attached, the cholera toxin can inject its toxic A subunit into the cell.

‘Optimally, one would bind all 5 B subunits to one inhibitor that uses this natural GM1 sugar,’ explains Han Zuilhof, from Wageningen University, the Netherlands, who led the work. ‘This should yield the strongest one-on-one complex. Previous work combined either pentavalent scaffolds with simpler sugars, or non-pentavalent scaffolds with the real deal sugar.’ Now, Zuilhof and colleagues have created the first inhibitor that is both pentavalent and uses GM1.

Read the full article in Chemistry World

And read the OBC paper here:
Picomolar inhibition of cholera toxin by a pentavalent ganglioside GM1os-calix[5]arene
Jaime Garcia-Hartjes, Silvia Bernardi, Carel A. G. M. Weijers, Tom Wennekes, Michel Gilbert, Francesco Sansone, Alessandro Casnati and Han Zuilhof

Digg This
Reddit This
Stumble Now!
Share on Facebook
Bookmark this on Delicious
Share on LinkedIn
Bookmark this on Technorati
Post on Twitter
Google Buzz (aka. Google Reader)

The 21st Lakeland meeting on Heterocyclic Chemistry and Synthesis, 40 years since the first meeting, was not to be missed!

Were you there?  Or you might have been following the live tweets from @Grasmere2013, updated by @APDobbs & @AzaPrins?

For a round up of the meeting and some highlight pictures, why not read below for a summary by this year’s organisers!

Grasmere 2013

The Heterocyclic Group began in 1967 and first held a Heterocyclic Conference in the Lake District village of Grasmere in May 1973. This meeting has been repeated every two years since, and the latest in this series took place 9-13th May 2013 and organised by Professors Adrian Dobbs (University of Greenwich) and David Knight (Cardiff University). 

This was a landmark for the meeting, marking 40 years since the first such meeting and the 21st meeting in the series – the ‘coming of age’ symposium! The original founder of the meeting, Professor Otto Meth-Cohn was in attendance and one member of the group, Professor Gurnos Jones has attended all 21 meetings.  As ever, lectures were held in Grasmere Village Hall and the conference booked-out two local hotels, as well as numberous B&B’s. Excellent science and food were in abundance during the meeting, as was the Lakeland rain, but a good time was had by all.

Highlights of the meeting included the presentations of two RSC Medals and their associated lectures: to Professor Scott Rychnovsky (UC Irvine, Pedler Medal) and Professor Chris Moody (University of Nottingham, Charles Rees Medal and Lecture).

Group photo outside Grasmere village Hall

Dr Robin Attrill (GSK); Prof Adrian Dobbs (Uni of Greenwich & Sec/Treasurer Heterocycli & Synthesis Group); Prof Scott Rychnovsky (recipient of the RSC Pedler Medal Award); Dr David Rees (Org Div President); Dr Marie Cote (Deputy Editor, OBC)

Prof Keith Jones (ICR); Prof Chris Moody (Uni of Nottingham, recipient of the RSC Charles Rees Award); Dr David Rees (Astex Pharmaceuticals)

Digg This
Reddit This
Stumble Now!
Share on Facebook
Bookmark this on Delicious
Share on LinkedIn
Bookmark this on Technorati
Post on Twitter
Google Buzz (aka. Google Reader)

HOT – New selenium compounds combat cancer

Synthetic indirubin derivatives can selectively inhibit cyclin-dependent kinases, stalling cancer growth and proliferation.
Peter Langer and co-workers hypothesised that selenoindirubins could have similar anti-proliferative effects. Selenoindirubins are scarcely reported in the literature, with only three examples known. This HOT article details an optimized synthesis for a series of selenoindirubins, alongside the first report of spectroscopic data for this class of compounds. A glycosyl moiety increased the pharmacological activity of indirubin derivatives and was incorporated into the selenoindirubin series to improve their solubility in DMSO and water. Members of this series had an anti-proliferative effect in lung cancer cells. Apoptosis was enhanced by combination treatment with the death ligand TRAIL, suggesting that selenoindirubins may have potential applications as anti-tumour agents.

Synthesis and antiproliferative activity of selenoindirubins and selenoindirubin-N-glycosides

Synthesis and antiproliferative activity of selenoindirubins and selenoindirubin-N-glycosides
Friedrich Erben, Dennis Kleeblatt, Marcel Sonneck, Martin Hein, Holger Feist, Thomas Fahrenwaldt, Christine Fischer, Abdul Matin, Jamshed Iqbal, Michael Plötz, Jürgen Eberle and Peter Langer
DOI: 10.1039/c3ob40603b

Free to access for 4 weeks

Digg This
Reddit This
Stumble Now!
Share on Facebook
Bookmark this on Delicious
Share on LinkedIn
Bookmark this on Technorati
Post on Twitter
Google Buzz (aka. Google Reader)

HOT – Unexpected Rearrangements of Biarylazacyclooctynones

Unexpected Rearrangement Reaction of Biarylazacyclooctynones

In this HOT paper, John Pezacki and co-workers report novel rearrangement and addition reactions of biarylazacyclooctynone (BARAC) leading to tetracyclic products. This behaviour may limit the practical applications of azacyclooctynones as bioorthogonal probes for biological systems.

Bioorthogonal reactions, i.e. reactions which can occur inside of a living system without interfering with native chemical processes, allow for the study of molecules such as proteins and lipids in vivo and in real time. The 1,3-dipolar cycloaddition between azides and octynes is an example of such a reaction. This copper-free variant of the Huisgen cycloaddition (better known as the click reaction) has been applied within cultured cells, live zebrafish and mice.

John Paul Pezacki and his research group at National Research Council Canada have been looking into these reactions and their application in biological probes and sensors. During their studies into the cycloaddition of azacyclooctynones such as BARAC (biarylazacyclooctynone), they noticed some interesting and unexpected results.

These molecules are able to undergo novel intramolecular cyclisation reactions which lead to the formation of tetracyclic products. Pezacki has performed some neat kinetics studies and computer-modelling, which have revealed that this rearrangement is accelerated by the presence of acid and that the linker side-chain also influences the rate of rearrangement.

This elegant, but rather unhelpful, reaction may limit the effectiveness of these molecules in biological systems, and this fascinating study illustrates how challenging it is to design effective bioorthogonal reactions.

Rearrangements and addition reactions of biarylazacyclooctynones and the implications to copper-free click chemistry
Mariya Chigrinova, Craig S. McKay, Louis-Philippe B. Beaulieu, Konstantin A. Udachin, André M. Beauchemin and John Paul Pezacki.
DOI: 10.1039/C3OB40683K

Free to access for 4 weeks

Digg This
Reddit This
Stumble Now!
Share on Facebook
Bookmark this on Delicious
Share on LinkedIn
Bookmark this on Technorati
Post on Twitter
Google Buzz (aka. Google Reader)

Chemical Biology and Medicinal: Synthesis of a selective inhibitor of a fucose binding bacterial lectin from Burkholderia ambifaria

Pathogen-associated lectins are considered to be attractive targets for the development of antiadhesive drugs. It is of great importance to design sugar-based derivatives able to selectively bind to specific pathogen-associated lectins with the aim of fighting bacterial infections without interfering with human lectins involved in physiological processes. 

Graphical Abstract

The stereoselective synthesis of the new fucose-based derivative 1, as the first example of glycomimetic selectively recognized by the fucose-binding lectin BambL from Burkholderia ambifaria is described.

Scientists in Italy report the first example of a synthetic ligand able to selectively bind, in the micromolar range, the pathogen-lectin BambL. BambL is a fucose-specific lectin from Burkholderia ambifaria, a bacterium member of the Burkholderia cepacia complex (BCC), a closely related group of Gram-negative bacteria responsible for cepacia syndrome in immunocompromised patients.

The fucose-based mimetic is therefore a promising candidate for the development of antibacterial agents against infection by B. ambifaria.

Synthesis of a selective inhibitor of a fucose binding bacterial lectin from Burkholderia ambifaria
Barbara Richichi, A Imberty, Emilie Gillon, Rosa Bosco, Ieva Sutkeviciute, Franck Fieschi and  Cristina Nativi  
Org. Biomol. Chem., 2013, Accepted Manuscript
DOI: 10.1039/C3OB40520F

Digg This
Reddit This
Stumble Now!
Share on Facebook
Bookmark this on Delicious
Share on LinkedIn
Bookmark this on Technorati
Post on Twitter
Google Buzz (aka. Google Reader)

OBC poster prizes at the 5th Chemical Protein Synthesis

Congratulations to Stijn Agten and Claudia Bello who both received OBC poster prizes at the 5th Chemical Protein Synthesis meeting in Vienna last month.

Stijn Agten, from the group of Professor Tilman Hackeng at Maastricht University, The Netherlands won for a poster entitled “Chemoselective reactions in proteins and peptides using an optimized oxime strategy: the demise of levulinic acid”, while Claudia Bello from the Institute of Biological Chemistry at University of Vienna presented a poster entitled “A Chemoenzymatic Approach for the Preparation of Site-Specifically O-Glycosylated MUC1 variants for Proteomic Studies”.

Both winners receive a year’s subscription to OBC.

Digg This
Reddit This
Stumble Now!
Share on Facebook
Bookmark this on Delicious
Share on LinkedIn
Bookmark this on Technorati
Post on Twitter
Google Buzz (aka. Google Reader)